In this proposal we will use mouse models that have mutations in the Cdk4 locus. Cdk4-/- mice are diabetic and lean, and in contrast, Cdk4R24C mice are non-diabetic and heavier. These observations are consistent with a role of the RB/E2F pathway in adipogenesis amd muscle differentiation. We hypothesize that Cdk4 activity may regulate adipogenesis and muscle development and function, and, by extension, overall energy balance. We are studying mechanisms of glucose tolerance and energy homeostasis by evaluating CDk4-dependent functions in different metabolic organs in the Cdk4 mice. The findings are revealing important role of Cdk4 in processes that modulate energy balance.